Role of Contacts in Capacitance Measurements of Solar Cells

The electronic properties of low cost, thin-film solar cells are complicated by the non-ideal nature of the semiconductor layers. Typically, the fundamental electronic properties of such materials are evaluated using current-voltage and capacitance-voltage measurements. However, in these devices, it is common for the back contact to be non-ohmic. We are exploring the impact of such a back contact on the outcome of standard capacitance-based characterization techniques. We compare computer models of capacitance response with measurements of simple model electronic circuits and of solar cell devices

Cas9 interrogates DNA in discrete steps modulated by mismatches and supercoiling.

The CRISPR-Cas9 nuclease has been widely repurposed as a molecular and cell biology tool for its ability to programmably target and cleave DNA. Cas9 recognizes its target site by unwinding the DNA double helix and hybridizing a 20-nucleotide section of its associated guide RNA to one DNA strand, forming an R-loop structure. A dynamic and mechanical description of R-loop formation is needed to understand the biophysics of target searching and develop rational approaches for mitigating off-target activity while accounting for the influence of torsional strain in the genome. Here we investigate the dynamics of Cas9 R-loop formation and collapse using rotor bead tracking (RBT), a single-molecule technique that can simultaneously monitor DNA unwinding with base-pair resolution and binding of fluorescently labeled macromolecules in real time. By measuring changes in torque upon unwinding of the double helix, we find that R-loop formation and collapse proceed via a transient discrete intermediate, consistent with DNA:RNA hybridization within an initial seed region. Using systematic measurements of target and off-target sequences under controlled mechanical perturbations, we characterize position-dependent effects of sequence mismatches and show how DNA supercoiling modulates the energy landscape of R-loop formation and dictates access to states competent for stable binding and cleavage. Consistent with this energy landscape model, in bulk experiments we observe promiscuous cleavage under physiological negative supercoiling. The detailed description of DNA interrogation presented here suggests strategies for improving the specificity and kinetics of Cas9 as a genome engineering tool and may inspire expanded applications that exploit sensitivity to DNA supercoiling

Nutritional Phases in Prader-Willi Syndrome: Evolutionary and Clinical Interpretations

Prader-Willi syndrome (PWS) is caused by a lack of expression of paternally-expressed imprinted genes at human chromosome 15q11–13 and is characterized by a switch from infant anorexia to childhood hyperphagia. A recent multiphase staging system recognizes gradual changes between the anorexic and hyperphagic phases of PWS. We undertook to use clinical records from an independent population to assess the multiphase system and explore the implications for the evolution of distinctive features of human childhood. Medical records of 258 clinic visits by 55 patients with PWS were reviewed with a focus on appetite and feeding. These clinical records were found to be inadequate for placing patients into particular stages of the multiphase system. Under the multiphase system, the onset of hyperphagia in PWS appears to coincide more with the timing of adrenarche than weaning from the breast and this timing should frame future evolutionary hypotheses. We discuss challenges encountered while attempting to use clinical data to explore evolutionary questions, but also identify useful information contained in the records.Organismic and Evolutionary Biolog

A pragmatic multi-centre randomised controlled trial of fluid loading in high-risk surgical patients undergoing major elective surgery - the FOCCUS study

Peer reviewedPublisher PD

The Aligned Orbit of the Eccentric Warm Jupiter K2-232b

Measuring the obliquity distribution of stars hosting warm Jupiters may help us to understand the formation of close-orbiting gas giants. Few such measurements have been performed due to practical difficulties in scheduling observations of the relatively infrequent and long-duration transits of warm Jupiters. Here, we report a measurement of the Rossiter-McLaughlin effect for K2-232 b, a warm Jupiter on an 11.17 day orbit with an eccentricity of 0.26. The data were obtained with the Automated Planet Finder during two separate transits. The planet's orbit appears to be well aligned with the spin axis of the host star, with a projected spin-orbit angle of λ = -11.°1 ± 6.°6. Combined with the other available data, we find that high obliquities are almost exclusively associated with planets that either have an orbital separation greater than 10 stellar radii or orbit stars with effective temperatures hotter than 6000 K. This pattern suggests that the obliquities of the closest-orbiting giant planets around cooler stars have been damped by tidal effects

Oncogenic KRAS engages an RSK1/NF1 pathway to inhibit wild-type RAS signaling in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with limited treatment options. Although activating mutations of the KRAS GTPase are the predominant dependency present in >90% of PDAC patients, targeting KRAS mutants directly has been challenging in PDAC. Similarly, strategies targeting known KRAS downstream effectors have had limited clinical success due to feedback mechanisms, alternate pathways, and dose-limiting toxicities in normal tissues. Therefore, identifying additional functionally relevant KRAS interactions in PDAC may allow for a better understanding of feedback mechanisms and unveil potential therapeutic targets. Here, we used proximity labeling to identify protein interactors of active KRAS in PDAC cells. We expressed fusions of wild-type (WT) (BirA-KRAS4B), mutant (BirA-KRAS4BG12D), and nontransforming cytosolic double mutant (BirA-KRAS4BG12D/C185S) KRAS with the BirA biotin ligase in murine PDAC cells. Mass spectrometry analysis revealed that RSK1 selectively interacts with membrane-bound KRASG12D, and we demonstrate that this interaction requires NF1 and SPRED2. We find that membrane RSK1 mediates negative feedback on WT RAS signaling and impedes the proliferation of pancreatic cancer cells upon the ablation of mutant KRAS. Our findings link NF1 to the membrane-localized functions of RSK1 and highlight a role for WT RAS signaling in promoting adaptive resistance to mutant KRAS-specific inhibitors in PDAC

<i>TESS</i> Spots a Compact System of Super-Earths around the Naked-eye Star HR 858

Transiting Exoplanet Survey Satellite (TESS) observations have revealed a compact multiplanet system around the sixth-magnitude star HR 858 (TIC 178155732, TOI 396), located 32 pc away. Three planets, each about twice the size of Earth, transit this slightly evolved, late F-type star, which is also a member of a visual binary. Two of the planets may be in mean motion resonance. We analyze the TESS observations, using novel methods to model and remove instrumental systematic errors, and combine these data with follow-up observations taken from a suite of ground-based telescopes to characterize the planetary system. The HR 858 planets are enticing targets for precise radial velocity observations, secondary eclipse spectroscopy, and measurements of the Rossiter–McLaughlin effect

A Three Species Model to Simulate Application of Hyperbaric Oxygen Therapy to Chronic Wounds

Chronic wounds are a significant socioeconomic problem for governments worldwide. Approximately 15% of people who suffer from diabetes will experience a lower-limb ulcer at some stage of their lives, and 24% of these wounds will ultimately result in amputation of the lower limb. Hyperbaric Oxygen Therapy (HBOT) has been shown to aid the healing of chronic wounds; however, the causal reasons for the improved healing remain unclear and hence current HBOT protocols remain empirical. Here we develop a three-species mathematical model of wound healing that is used to simulate the application of hyperbaric oxygen therapy in the treatment of wounds. Based on our modelling, we predict that intermittent HBOT will assist chronic wound healing while normobaric oxygen is ineffective in treating such wounds. Furthermore, treatment should continue until healing is complete, and HBOT will not stimulate healing under all circumstances, leading us to conclude that finding the right protocol for an individual patient is crucial if HBOT is to be effective. We provide constraints that depend on the model parameters for the range of HBOT protocols that will stimulate healing. More specifically, we predict that patients with a poor arterial supply of oxygen, high consumption of oxygen by the wound tissue, chronically hypoxic wounds, and/or a dysfunctional endothelial cell response to oxygen are at risk of nonresponsiveness to HBOT. The work of this paper can, in some way, highlight which patients are most likely to respond well to HBOT (for example, those with a good arterial supply), and thus has the potential to assist in improving both the success rate and hence the cost-effectiveness of this therapy

Decreased transcription-coupled nucleotide excision repair capacity is associated with increased p53- and MLH1-independent apoptosis in response to cisplatin

Abstract Background One of the most commonly used classes of anti-cancer drugs presently in clinical practice is the platinum-based drugs, including cisplatin. The efficacy of cisplatin therapy is often limited by the emergence of resistant tumours following treatment. Cisplatin resistance is multi-factorial but can be associated with increased DNA repair capacity, mutations in p53 or loss of DNA mismatch repair capacity. Methods RNA interference (RNAi) was used to reduce the transcription-coupled nucleotide excision repair (TC-NER) capacity of several prostate and colorectal carcinoma cell lines with specific defects in p53 and/or DNA mismatch repair. The effect of small inhibitory RNAs designed to target the CSB (Cockayne syndrome group B) transcript on TC-NER and the sensitivity of cells to cisplatin-induced apoptosis was determined. Results These prostate and colon cancer cell lines were initially TC-NER proficient and RNAi against CSB significantly reduced their DNA repair capacity. Decreased TC-NER capacity was associated with an increase in the sensitivity of tumour cells to cisplatin-induced apoptosis, even in p53 null and DNA mismatch repair-deficient cell lines. Conclusion The present work indicates that CSB and TC-NER play a prominent role in determining the sensitivity of tumour cells to cisplatin even in the absence of p53 and DNA mismatch repair. These results further suggest that CSB represents a potential target for cancer therapy that may be important to overcome resistance to cisplatin in the clinic

Generation in vivo of peptide-specific cytotoxic T cells and presence of regulatory T cells during vaccination with hTERT (class I and II) peptide-pulsed DCs

Optimal techniques for DC generation for immunotherapy in cancer are yet to be established. Study aims were to evaluate: (i) DC activation/maturation milieu (TNF-α +/- IFN-α) and its effects on CD8+ hTERT-specific T cell responses to class I epitopes (p540 or p865), (ii) CD8+ hTERT-specific T cell responses elicited by vaccination with class I alone or both class I and II epitope (p766 and p672)-pulsed DCs, prepared without IFN-α, (iii) association between circulating T regulatory cells (Tregs) and clinical responses